By Mark I. Schwartz –
On June 23, 2017 FDA published a notice in the Federal Register entitled: “Submission of Proposed Recommendations for Industry on Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing; Establishment of a Public Docket”. This notice relates to a workshop FDA hosted on the future of pharmaceutical manufacturing in 2015, where FDA had recommended that interested parties submit draft guidance or other materials discussing best practices related to so-called “continuous manufacturing.”
Since then, the Center for Structured Organic Particulate Systems (C-SOPS) submitted to FDA an industry coordinated best practices document on continuous manufacturing, entitled “Current Recommendations for Implementing and Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing”. FDA is now interested in receiving public comments about the practices discussed in the C-SOPS document and hence has opened a docket for that purpose. FDA is also interested in receiving comments and other recommendations regarding continuous manufacturing, particularly on control strategy, facility, and process validation considerations for continuous manufacturing of solid oral dosage forms.
Pharmaceutical manufacturing can be classified into one of three categories, all based on how the materials enter and leave the manufacturing process: batch, semi-continuous and continuous. Historically, pharmaceutical operations have been performed by the batch process, known as batch manufacturing, which involves sequentially loading a fixed amount of material into the first part of the manufacturing process, processing that material, and then discharging that material in preparation for the next phases of manufacturing, which could take place weeks, or months, later.
Continuous manufacturing, on the other hand, involves material constantly being loaded, processed and unloaded without interruption through the various phases of the manufacturing process. Semi-continuous manufacturing has elements of both batch and continuous manufacturing in that materials are either constantly loaded or constantly removed from the manufacturing process, though not without interruption (for more information on these processes please see C-SOPS’ “Current Recommendations for Implementing and Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing”).
For years now, FDA has been encouraging manufacturers to switch from traditional batch manufacturing to continuous manufacturing, based on the premise that batch manufacturing processes are outdated (they have not changed in well over fifty years), and that continuous manufacturing is more reliable, safer, more efficient (i.e., can drive down manufacturing costs), and allows manufacturers to respond much quicker to changes in demand, thereby theoretically reducing the likelihood of drug shortages (see, for example, FDA’s slide presentation from January 2012, at the IFPAC Meeting in Baltimore, Maryland, entitled “FDA Perspective on Continuous Manufacturing”).
Indeed, the agency has had a couple of successes in this regard. For instance, in July 2015, FDA approved Vertex’s cystic fibrosis drug called Orkambi (lumacaftor/ivacaftor) on the basis of the firm’s continuous manufacturing process and, in April of 2016, for the first time, FDA approved a manufacturer’s change in its production method from batch to continuous manufacturing for its previously approved product – Janssen’s HIV drug Prezista (darunavir).
However, despite many years of FDA encouragement, much of the pharmaceutical industry has seemed reluctant to jump head first into the realm of continuous manufacturing. There appear to be at least a couple of reasons for this. For previously approved products, manufacturers might be reluctant to submit a supplement to modify the existing type of manufacturing in order to produce the same product the firm is already marketing lest the agency raise concerns with the new continuous manufacturing process, and thereby short circuit the planned phase-out of the old method of manufacturing (i.e., regulatory uncertainty).
For products yet to be approved by FDA, there is the impediment of a significant capital investment in the new equipment specifically designed for continuous manufacturing, particularly when the benefits, described above, appear speculative and, to the extent they are not speculative, the monetary rewards may not allow for the recouping of the capital investment (i.e., uncertain economic benefit).
One question that has been frequently raised within industry circles is whether FDA’s cGMP regulations at 21 CFR Part 210 and 211 are entirely compatible with the concept of continuous manufacturing and, hence, whether this could create a regulatory problem for firms that switch to continuous manufacturing. FDA has long maintained that the regulations are entirely compatible with this new form of drug manufacturing, despite the fact that the regulations are built around the concept of a “batch” (for instance, see the FDA slide presentation from the IFPAC meeting mentioned above). Examples of cGMP regulations in the 211s that reference important concepts related to batch or lot manufacturing include 21 CFR 211.150(b), 211.165(a), 211.188, and 211.192.
Indeed, FDA has stated that the term “batch” in the regulations refers to the “quantity of material” and not the “mode of manufacture” and has added that FDA’s quality by design efforts would benefit to a greater extent from the more modern manufacturing approach, as it has a greater potential to improve the quality assurance of drug manufacturing.
In terms of Federal action in this area thus far, FDA published a guidance document in December 2015, which tangentially relates to this issue, entitled “Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base.” It provides recommendations to pharmaceutical firms interested in participating in a program involving the submission of CMC information containing emerging manufacturing technology to FDA. Also, the 21st Century Cures Act authorizes HHS to award grants to academic institutions and nonprofit organizations to study and recommend improvements to the process of continuous manufacturing of drugs and biologics (section 3016).
We will continue to update our readers on this emerging area of pharmaceutical manufacturing, and will soon publish an overview of the recommendations that were made by C-SOPS.
Batch Manufacturing or Continuous Manufacturing? – That is the Question
By Mark I. Schwartz –